Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of the joints, producing pain and ultimate destruction of the joints. Rheumatoid arthritis is characterized by a chronic inflammatory response in the joint that is directed by macrophages and T cells which invade affected joints. Production of proinflammatory cytokines and other immune cell mediators by these immune cells results in the development of a proliferative invasive connective tissue derived from the synovial membrane and its microvasculature that slowly erodes away the cartilage and bone tissues of joints.
While destruction of joint tissue is the most common feature of RA, the disease can exhibit significant extra-articular manifestations, including cutaneous lesions, vasculitis, blood abnormalities, peripheral neuropathy, pericarditis, arteritis of the viscera, and pulmonary disease. This indicates that RA is a systemic disease that affects the connective tissues of major organs systems. The specific etiology of RA remains elusive. Dysregulation of both cell-mediated and humoral immunity are associated with RA. The pathophysiology of RA intimately involves defects in immune cell regulation. Although the exact mechanisms have not been delineated, the functional activities of macrophages, B cells and T cells from both the joint and lymphoid tissue are affected.
Unfortunately, current treatment strategies for RA and other inflammatory autoimmune diseases are relatively ineffective in preventing bone destruction. Conventional anti-rheumatic drugs are classified into anti-inflammatory drugs, slow-acting drugs and corticosteroids. Only the slow-acting drugs are thought to be capable of modifying the disease course of rheumatoid arthritis and are referred to as disease modifying anti-rheumatic drugs (DMARD). Drugs from each of these classes are currently being used for treatment of rheumatic diseases. Of these, the central focus has been and remains the DMARDS and nonsteroidal anti-inflammatory drugs (NSAID). NSAIDs effectively abolish the signs and symptoms of joint inflammation and reduce pain. They are not effective in preventing bone and cartilage loss. The value of NSAIDs for treating rheumatic diseases is limited by their side effects.
Aggressive rheumatoid arthritis or early onset of joint destruction indicates the need for rapid treatment with DMARDs. Use of one second-line drug followed by another once the drug being used is no longer effective or is not tolerated well by the patient, is most widely practiced by rheumatologists. Methotrexate and other immunosuppressive drugs, such as cyclosporin and leflunomide were major advancements of the 1980s in treating rheumatoid arthritis. Methotrexate is currently the gold standard for treatment of aggressive rheumatoid arthritis. However, its effectiveness wanes over time and can cause troublesome side effects, including liver damage, sepsis, severe anemia and bleeding.
The approved immunosuppressive drug, leflunomide, was introduced for treating rheumatoid arthritis. This drug relieves joint tenderness and swelling, decreases joint pain and reduces indicators of global disease activity. While leflunomide does not make patients more susceptible to infections, it can cause hair loss, weight loss, hypertension, dizziness, and gastrointestinal side effects. Advances in management of rheumatoid arthritis include the use of corticosteroids as anti-inflammatory and immunosuppressive agents. The main disadvantage of corticosteroids is that long-term use is limited due to adverse effects including weight gain, hyperglycemia, cataracts, osteoporosis, and stomach ulcers.
Thus, treatment for patients with rheumatoid arthritis is imperfect. Accordingly, there is an urgent need for treatments which have few if any side effects and that will be effective in suppressing not only the inflammation but also prevent the bone and cartilage degeneration associated with rheumatoid arthritis.